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An important study showing that familial ALS has no formal or informal definition, with a wide range of opinions between physicians.
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This study, along with Hirano et al. (reference 105), Le Ber et al. (reference 106) and Rubino et al. (reference 107), showed that as well as TDP-43, sequestosome-1, another component of ubiquitin-immunoreactive inclusions in ALS, could be a primary cause of ALS, and also provided evidence that the proteasome system is important for motor neuron health.
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This key paper, along with Renton et al. (reference 46), provided the first identification of the most frequent cause of ALS, pathological expansion of a repeat in intron 1 of the C9orf72 gene. This finding was confirmed in linkage studies by Morita et al. (reference 39) and Vance et al. (reference 40), and in association studies by van Es et al. (reference 31) and Shatunov et al. (reference 32).
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A study that used multiple methods, including machine learning and gene sequencing in isolated populations, to identify an ALS-associated gene.
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A large genome-wide association study that found four new ALS loci, thee of which were replicated by the authors. The study also showed that rare genetic variants are disporportionately important in ALS.
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References 39 and 40 showed, for the first time, that ALS and frontotemporal dementia should — at least in some cases — be considered as related diseases.
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This study links the most frequent pathological finding in ALS, TDP-43 protein accumulation, with a genetic variation that cannot be detected with conventional genome-wide association methods — a trinucleotide repeat in a spinocerebellar ataxia-associated gene, which causes ALS when pathologically expanded to an intermediate size.
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A superb genetic and statistical analysis of the genome, providing a framework for the interpretation of exome sequence changes.
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This study, along with Kabashi et al. (reference 22), showed that TDP-43, a protein found as a pathological accumulation in motor neurons in 98% of cases of ALS, could be a primary cause of the disease, and was not just a downstream manifestation of the disease process. The study also highlighted, for the first time, that RNA-processing defects could result in motor neuron degeneration.
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The finding of an oligogenic component in a significant percentage of ALS cases has implications for genetic counselling, and provides evidence of an additive effect of gene variations.
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A large European study showing that ALS is a multistep process like cancer, and requires, on average, six molecular steps, at least one of which is likely to be genetic in most people.
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An important step in the development of personalized, gene-based therapies for ALS.
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